The invention relates to a process for the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula I: 
The compound of formula I is known and described in WO 99/65920. It is useful for the treatment and prophylaxis of infectious diseases, especially infectious diseases caused by bacterial pathogens, in particular, methicillin resistent Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. 
a) oxidation of a 3-hydroxymethyl-cephem derivative to the corresponding 3-formyl-cephem derivative;
b) reaction of said compound with the ylide of 1-substituted 2-oxo-pyrrolidin compounds to 3-vinyl-pyrrolidone cephem derivatives;
c) deprotection and reaction with 5-amino-[1,2,4]thiadiazol-3-yl)-trityloxyimino-thioacetic acid S-benzothiazol-2-yl ester;
d) deprotection reactions; and
e) subsequent acylation reaction with carbonic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 4-nitro phenyl ester.
The present invention is a process for the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula I 
which process comprises:
acylating a compound of formula II 
with a compound of formula III 
wherein R1 is a hydroxy protecting group and Y is an activating group of formula Y1
or of formula Y2
or of formula Y3, 
in the presence of a base, and protecting of the carboxylic acid group to form a compound of formula IV 
wherein R2 is a carboxylic acid protecting group;
oxidizing the compound of formula IV with an inorganic hypohalite in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) or with manganese dioxide, to obtain the corresponding aldehyde derivative of formula V 
reacting the compound of formula V with the ylide of the phosphonium salt of formula VI 
wherein Ph is phenyl and R is an amino protecting group or a group of formula A 
to form a cephalosporine derivative of formula Ia 
and;
i) when R is an amino protecting group, cleaving off the protecting groups R1, R2 and R, and reacting the resulting unprotected compound with a compound of formula VII 
to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I; or
ii) when R is a group of formula A, cleaving off the hydroxy and the carboxylic acid protecting groups R1 and R2 under acidic conditions to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I.
The present invention also provides a compound of formula IV 
wherein R1 is a hydroxy protecting group and R2 is a carboxylic acid protecting group.
In addition, the present invention provides a compound of formula V 
wherein R1 is a hydroxy protecting group and R2 is a carboxylic acid protecting group.
Compounds IV and V are intermediates in the process of preparing the compound of formula I, in accordance with the present invention.
It has been found that the compound of formula I can be manufactured in an improved way by the process of the present invention. The process of the present invention for the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula I 
is characterized in that it comprises
step (a) acylating a compound of formula II 
with a compound of formula III 
wherein R1 is a hydroxy protecting group and Y is an activating group, as for example a group of formula Y1
or of formula Y2
or of formula Y3, 
in the presence of a base, and subsequently protecting the carboxylic acid group to form the product of formula IV 
wherein R1 is as defined above and R2 is a carboxylic acid protecting group;
step (b) oxidizing the compound of formula IV with an inorganic hypohalite in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) or with manganese dioxide, to obtain the corresponding aldehyde derivative of formula V 
wherein R1 and R2 are as defined above;
step (c) reacting the compound of formula V with the ylide of the phosphonium salt of formula VI 
wherein Ph is phenyl and R is an amino protecting group or a group of formula A 
to form the cephalosporine derivatives of formula Ia 
wherein R1, R2 and R are as defined above; and
step (d) i) when R is an amino protecting group, cleaving off the protecting groups R1, R2 and R, and reacting the unprotected compound subsequently with a compound of formula VII 
to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I; or
ii) when R is a group of formula A, cleaving off the hydroxy and the carboxylic acid protecting groups R1 and R2 under acidic conditions to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I.
It has been surprisingly found, that due to the combination of process steps according to the invention, formula I is prepared by fewer steps and is obtained in higher yield, thereby decreasing production costs.
In the structural formulae presented herein a wedged bond () denotes that the substituent is above the plane of the paper.
The term xe2x80x9chydroxy protecting groupxe2x80x9d as used herein denotes an alkyl group, a cycloalkyl group or an arylalkyl group. A preferred hydroxy protecting group is an arylalkyl group, especially preferred is a triphenylmethyl (trityl) group.
The term xe2x80x9cactivating groupxe2x80x9d as used herein denotes, for example, an activated ester such as a group of formula Y1 (mercaptobenzothiazole thioester) as described in EP 0849269 or of formula Y2 (1-hydroxybenzotriazole esters) or mixed anhydrides in analogy to those described in EP 0812846 such as Y3 (diethyl thiophosphoryl) or acid halides, in particular, acid chlorides in analogy to those described in J. Antibiot. (1984), 37(5), 557-71, which increase the reactivity of the carbon atom of the oxo group of the compound of formula III. The acylation of the compound of formula II with an activated compound of formula III results in a higher yield. A preferred activating group is the mercaptobenzothiazole thioester group.
The term xe2x80x9cbasexe2x80x9d as used herein (step (a)) denotes a common base such as a tertiary amine, amidine base or a guanidine base.
The term xe2x80x9ctertiary aminexe2x80x9d as used herein denotes a group of formula N(alkyl)3 in which the same or different alkyl groups are attached to the nitrogen atom. Examples are trimethyl amine, triethyl amine, dimethyl ethyl amine, methyl diethyl amine, tripropyl amine or tributyl amine.
The term xe2x80x9camidine basexe2x80x9d as used herein denotes amidines or alkyl amidines in which 1, 2 or 3 hydrogen(s) are substituted by the same or different alkyl groups potentially also forming rings. Preferred amidine bases are 1,8-diazabicyclo[5.4.0]undec-7-en (DBU) and 1,8-diazabicyclo[4.3.0]non-5-en (DBN).
The term xe2x80x9cguanidine basexe2x80x9d as used herein denotes guanidine or alkyl guanidine in which 1, 2, 3, 4 or 5 hydrogen(s) (in the 1, 2 or 3-position) are substituted by the same or different alkyl group, potentially also forming rings. Preferred guanidine bases are alkyl guanidine bases such as 1,1,3,3-tetramethyl guanidine.
The term xe2x80x9calkylxe2x80x9d as used herein denotes a straight or branched chain hydrocarbon residue containing 1 to 7 carbon atoms, such as methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert.-butyl and the like.
The term xe2x80x9calkoxyxe2x80x9d signifies an alkyl group as defined above which is bonded via an oxygen atom. Examples are methoxy, ethoxy, propyloxy, butoxy and the like.
By the term xe2x80x9ccycloalkylxe2x80x9d as used herein denotes a 3-7 membered saturated carbocyclic moiety, e.g., cyclopropyl, cyclobutyl, cyclopentyl , cyclohexyl or cycloheptyl.
The term xe2x80x9carylxe2x80x9d as used herein denotes a phenyl group or a monosubstituted phenyl group which is substituted in the ortho-, meta- or para- position. Such substituents for the phenyl group are C1-4-alkyl groups.
The term xe2x80x9caryloxyxe2x80x9d signifies an aryl group as defined above which is bonded via an oxygen atom. Examples are phenyloxy and the like.
The term xe2x80x9carylalkylxe2x80x9d as used herein denotes a hydrocarbon group in which one or more alkyl hydrogen atoms are substituted by an aryl group such as trityl or benzhydryl.
The term xe2x80x9ccarboxylic acid protecting groupxe2x80x9d includes protecting groups which are usually used to replace a proton of the carboxyl group. Examples of such groups are described in Green T., Protective Groups in Organic Synthesis, Chapter 5, John Wiley and Sons, Inc. (1981), pp. 152-192. Known examples of such protecting groups are: benzhydryl, tert.-butyl, p-nitrobenzyl, p-methoxybenzyl, methoxymethyl and the like. Benzhydryl is a preferred carboxylic acid protecting group.
The term xe2x80x9camino protecting groupxe2x80x9d as used herein includes groups usually used to replace one proton or both protons of the amino group, such as those employed in peptide chemistry. Examples of such groups are described in Green T., Protective Groups in Organic Synthesis, Chapter 5, John Wiley and Sons, Inc. (1981), pp. 218-287, such as allyloxycarbonyl (ALLOC), an alkoxycarbonyl group such as tert.-butoxycarbonyl (t-BOC) and the like; a substituted alkoxycarbonyl group such as trichloroethoxycarbonyl; an optionally substituted aryloxycarbonyl group, for example, p-nitrobenzyloxycarbonyl or benzyloxycarbonyl; an arylalkyl group such as trityl (triphenylmethyl) or benzhydryl; an alkanoyl group such as formyl or acetyl; a halogen-alkanoyl group such as chloroacetyl, bromoacetyl, iodoacetyl or trifluoroacetyl; or a silyl protective group such as the trimethylsilyl group. Preferred amino protecting groups are tert.-butoxycarbonyl or allyloxycarbonyl.
The term xe2x80x9calkoxycarbonylxe2x80x9d denotes an alkoxy residue attached to a carbonyl group (Cxe2x95x90O). Examples are methoxycarbonyl, ethoxycarbonyl, propoxycarbonyl, tert.-butoxycarbonyl and the like.
The term xe2x80x9caryloxycarbonylxe2x80x9d denotes an aryloxy residue attached to a carbonyl group (Cxe2x95x90O). An example is benzyloxycarbonyl.
The term xe2x80x9cacidic conditionsxe2x80x9d as used herein denotes a pH of the reaction mixture in the range of 1 to 7, preferably in the range of 2 to 6. An especially preferred pH is in the range of 3 to 6.
The term xe2x80x9cinorganic hypohalitesxe2x80x9d as used herein denotes a compound such as sodium hypochlorite, potassium hypochlorite, calcium hypochlorite or sodium hypobromite. An especially preferred inorganic hypohalite is sodium hypochlorite.
In the first step of the process, a solution of a compound of formula II (preparation as described in DE 2128605) in an appropriate solvent is treated with a base, for example, a tertiary amine, an amidine or a guanidine base. A preferred base is an alkylated guanidine base. An especially preferred guanidine base is the commercially available 1,1,3,3-tetramethyl-guanidine. Appropriate solvents are polar aprotic solvents such as dimethylsulfoxid (DMSO), dimethylacetamide or N,N-dimethylformamid (DMF), preferably DMF. The solution is cooled to a temperature between about xe2x88x9220xc2x0 C. and about +50xc2x0 C., preferably to 0xc2x0 C., and treated with a compound of formula III (preparation described for Y1 in EP 0 849 269; Y2: preparation in analogous manner as described in U.S. Pat. No. 5,672,711; Y3: preparation in analogous manner as described in EP 0 812 846) to obtain the acylation product. To protect the carboxylic acid group, the solution is subsequently diluted with water, washed with ethylacetate and the resulting aqueous layer is mixed with a halogenated hydrocarbon, such as CH2Cl2. The aqueous solution is cooled to a temperature between about xe2x88x925xc2x0 C. and about +35xc2x0 C., preferably to 0xc2x0 C. and reacted with diphenyldiazomethane (available from Sigma Aldrich) at a pH in the range of 1 to 9, preferably at a pH in the range of 1 to 7, more preferred at a pH in the range of 2 to 5, especially preferred at pH 3, to obtain the carboxylic acid protected compound of formula IV. After extraction, the compound of formula IV is isolated by rapid precipitation with a hydrocarbon such as pentane or hexane.
Also part of the present invention is a process for the preparation of a compound of formula IV 
wherein R1 is a hydroxy protecting group and R2 is a carboxylic acid protecting group, which process is characterized in that it comprises
step (a) acylating a compound of formula II 
with a compound of formula III 
wherein R1 is as defined above and Y is an activating group of formula Y1
or of formula Y2
or of formula Y3, 
in the presence of a base, and subsequently protecting the carboxylic acid group to form the product of formula IV.
The compounds of formula IV are encompassed by the present invention. The compounds of formula IV may be used for the preparation of the vinyl-pyrrolidinone cephalosporine derivative of formula I 
In the second step, the compound of formula IV is dissolved in an appropriate solvent and oxidized with a 20-100 molar excess (relative to the compound of formula IV) of manganese dioxide. Appropriate solvents are ethers such as tert.-butyl methyl ether (TBME) or tetrahydofurane (THF) or halogenated hydrocarbons such as CH2Cl2, preferably a mixture of such solvents. An especially preferred mixture is tetrahydofurane and dichloromethane.
In a preferred embodiment of the invention (step 2), the compound of formula V may also be obtained by the following way: A solution of the compound of formula IV in an appropriate solvent is treated with an inorganic salt such as KBr and a basic inorganic salt such as NaHCO3 in water, cooled to a temperature between about xe2x88x925xc2x0 C. and about +35xc2x0 C., preferably a temperature of 0xc2x0 C., treated with 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) (available from Fluka), and oxidized with an inorganic hypohalite such as sodium hypochlorite, potassium hypochlorite, calcium hypochlorite, sodium hypobromite, preferably sodium hypochlorite (J. Org. Chemistry, Vol 56, 1991, page 2416-2421). Appropriate solvents are ethers such as tert.-butyl methyl ether (TBME), esters such as ethyl acetate (AcOEt), hydrocarbons such as toluene or halogenated hydrocarbons, preferably CH2Cl2.
Also part of the present invention is a process for the preparation of a compound of formula V 
wherein R1 is as defined above and R2 is a carboxylic acid protecting group, which process is characterized in that it comprises oxidizing the compound of formula IV 
wherein R1 and R2 are as defined above, with an inorganic hypohalite in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) or with manganese dioxide to obtain the corresponding aldehyde derivative of formula V.
The compounds of formula V are encompassed by the present invention. The compounds of formula V may be used for the preparation of the vinyl-pyrrolidinone cephalosporine derivative of formula I.
In the third step, the phosphonium salt of formula VI (preparation see below) is dissolved in an appropriate solvent and reacted with a strong base to form the corresponding ylide. Appropriate bases are t-C4H9OK, LiN(Si(CH3)3)2 or lithium diisopropylamide (LDA), preferably t-C4H9OK, which are dissolved in ethers, such as THF. Appropriate solvents are hydrocarbons such as toluene, halogenated hydrocarbons such as CH2Cl2, ethers such as THF or any combination of toluene, CH2Cl2 and THF. The resulting ylide in solution is reacted with a solution of the compound of formula V dissolved in an ether, such as THF, to form the cephalosporine derivatives of formula Ia. The reaction temperature is between about xe2x88x92120xc2x0 C. and about +35xc2x0 C., preferably between about xe2x88x92100xc2x0 C. and about +30xc2x0 C., most preferred at a temperature of xe2x88x9270xc2x0 C.
Compounds of formula VI wherein R is an amino protecting group are prepared according to EP-A-0 849 269.
In the following the preparation of a compound of formula VI (wherein R is a group of formula A: compound VI-a) is described, which is used for the preparation of compounds of formula Ia (3rd step). 
The compound of formula VI-a is prepared in that a mixture of (1R,3xe2x80x2R) and (1S,3xe2x80x2R)-(1xe2x80x2-allyloxycarbonyl-2-oxo-[1,3xe2x80x2]bipyrrolidinyl-3-yl)-triphenyl-phosphonium bromide (prepared according to EP-A-0849269) is dissolved in an appropriate solvent and deprotected, for example, with bis-(triphenylphosphine)palladium dichloride, acetic acid and tributyltin hydride or equivalent methods known from the literature (e.g. J. March (1992), xe2x80x9cAdvanced Organic Chemistry: Reactions, Mechanisms and Structurexe2x80x9d, 4th ed. John Wiley and Sons) to form the free bipyrrolidinyl compound. Appropriate solvents are hydrocarbons such as toluene or halogenated hydrocarbons, preferably CH2Cl2. The resulting intermediate is dissolved in hydrocarbons such as toluene or halogenated hydrocarbons such as CH2Cl2, and reacted with carbonic acid 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 4-nitro phenyl ester (preparation described in U.S. Pat. No. 5,466,811) to yield to a mixture of (3R,3xe2x80x2R) and (3S,3xe2x80x2R) [1xe2x80x2-(5-methyl-2-oxo-[1,3]dioxol-4-ylmethoxycarbonyl)-2-oxo-[1,3xe2x80x2]bipyrrolidinyl-3-yl]-triphenyl-phosphonium bromide (compound of formula VI-a).
The compound of formula VI-a is encompassed by the present invention. The compound of formula VI-a can be used for the preparation of the vinyl-pyrrolidinone cephalosporine derivative of formula I.
In the fourth step, the compound of formula Ia (when R is an amino protecting group) is deprotected with trialkylsilane, preferably triethylsilane in an amount between 1-5 equivalents (relative to compound of formula Ia) or by a combination of anisole in an amount between 1-50 equivalents (relative to compound of formula Ia), formic acid in an amount between 1-50 equivalents (relative to compound of formula Ia) and trifluoroacetic acid in an amount between 0.1-5 equivalents (relative to compound of formula Ia) in an appropriate solvent. Appropriate solvents are ethers such as THF, or halogenated hydrocarbons such as dichloromethane. The reaction is carried out at a temperature between about xe2x88x9230xc2x0 C. and about 60xc2x0 C., preferably at a reaction temperature of 30xc2x0 C. The deprotected compound of formula Ia (when R is hydrogen) is subsequently reacted with 5-methyl-2-oxo-[1,3]dioxol-4-ylmethyl ester 4-nitro phenyl ester (preparation as described in U.S. Pat. No. 5,466,811) according the method as described in WO 99/65920 to obtain vinyl-pyrrolidinone cephalosporine derivative of formula I.
In an alternative fourth step, the hydroxy and carboxylic acid protecting groups of the compound of formula Ia (when R is a group of formula A) are cleaved under acidic conditions to obtain the vinyl-pyrrolidinone cephalosporine derivative of formula I. A mixture of the compound of formula Ia (when R is a group of formula A) and trialkylsilane, preferably triethylsilane, in an amount between 1-10 equivalents (relative to the compound of formula Ia), preferably in an amount between 4-6 equivalents, is dissolved in trifluoroacetic acid or a mixture of trifluoroacetic acid and a halogenated hydrocarbon such as dichloromethane in an amount of trifluoroacetic acid between 50-150 equivalents (relative to the compound of formula Ia), preferably in an amount between 85-115 equivalents. The reaction temperature is between about xe2x88x925xc2x0 C. and about 20xc2x0 C., more preferably the reaction temperature is 0xc2x0 C., and the compound of formula I is obtained after a reaction time which varies between 5 and 60 min.
In a preferred embodiment of the invention, the substituent R1 is triphenylmethyl, R2 is benzhydryl, tert.-butyl, p-nitrobenzyl, p-methoxybenzyl or methoxymethyl, R is tert.-butoxycarbonyl or allyloxycarbonyl and Y is a group Y1. In an especially preferred embodiment, R1 is triphenylmethyl, R2 is benzhydryl, R is tert.-butoxycarbonyl and Y is a group Y1.
In a further preferred embodiment of the process of the invention, R1 is triphenylmethyl, R2 is benzhydryl, tert.-butyl, p-nitrobenzyl, p-methoxybenzyl or methoxymethyl, R is a group of formula A and Y is a group Y1. Especially preferred is a process wherein R1 is triphenylmethyl, R2 is benzhydryl, R is a group of formula A and Y is a group Y1.
The vinyl-pyrrolidinone cephalosporine derivative of formula I obtained through the process as described in the invention may be used for the preparation of a pharmaceutical composition, for example, in the form of pharmaceutical preparations for parenteral administration. For this purpose the vinyl-pyrrolidinone cephalosporine derivative of formula I is preferably made into preparations as lyophilisates or dry powders for dilution with customary agents, such as water or isotonic common salt or carbohydrate (e.g. glucose) solution.
The pharmaceutical preparations may contain the vinyl-pyrrolidinone cephalosporine derivative of formula I for the prevention and treatment of infectious diseases in mammals, human and non-human. A daily dosage of about 10 mg to about 4000 mg, especially about 50 mg to about 3000 mg, is usual, with those of ordinary skill in the art appreciating that the dosage will depend also upon the age, conditions of the mammals, and the kind of diseases being prevented or treated. The daily dosage can be administered in a single dose or can be divided over several doses. An average single dose of about 50 mg, 100 mg, 250 mg, 500 mg, 1000 mg, and 2000 mg can be contemplated.
A further embodiment of the process of the invention is the preparation of a vinyl-pyrrolidinone cephalosporine derivative of formula Ia 
wherein R1 is a hydroxy protecting group, R2 is a carboxylic acid protecting group and R is an amino protecting group
which is characterized in that it comprises
step (a) acylating a compound of formula II 
with a compound of formula III 
wherein R1 is a hydroxy protecting group and Y is an activating group, as for example, a group of formula Y1
or of formula Y2
or of formula Y3, 
in the presence of a base, and subsequently protecting the carboxylic acid group
to form the product of formula IV 
wherein R1 and R2 are as defined above;
step (b) oxidizing the compound of formula IV with an inorganic hypohalite in the presence of 2,2,6,6-tetramethyl-1-piperidinyloxyl radical (TEMPO) or with manganese dioxide to obtain the corresponding aldehyde derivative of formula V 
wherein R1 and R2 are as defined above;
step (c) reacting the compound of formula V with the ylide of the phosphonium salt of formula VI 
wherein Ph is phenyl and R is an amino protecting group or a group of formula A 
to form the cephalosporine derivatives of formula Ia.
In a preferred embodiment of the invention, the substituent R1 is triphenylmethyl, R2 is benzhydryl, tert.-butyl, p-nitrobenzyl, p-methoxybenzyl or methoxymethyl, R is tert.-butoxycarbonyl, allyloxycarbonyl or a group of formula A and Y is a group Y1. Especially preferred is that R1 is triphenylmethyl, R2 is benzhydryl, R is tert.-butoxycarbonyl or a group of formula A and Y is a group Y1.
The compounds of formula I prepared according to the invention may be used for the treatment and prophylaxis of infectious diseases, especially infectious diseases caused by bacterial pathogens, in particular, methicillin resistent Staphylococcus aureus (MRSA) and Pseudomonas aeruginosa. 
In the following examples the abbreviations used have the following significations.
All temperatures are given in degrees Celsius (xc2x0 C.).